Identification of human cytochrome P450 and flavin-containing monooxygenase enzymes involved in the metabolism of lorcaserin, a novel selective human 5-hydroxytryptamine 2C agonist

Drug Metabolism and Disposition

Volumn 40, Issue 4, 2012, Pages 761-771

  Usmani, Khawja A ^a   Chen, Weichao G ^a,b   Sadeque, Abu J M ^a  

^a ARENA PHARMACEUTICALS   (United States)

^b VERTEX PHARMACEUTICALS   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 HYDROXYLORCASERIN; 5 HYDROXYLORCASERIN; 7 HYDROXYLORCASERIN; CYTOCHROME P450; CYTOCHROME P450 1A1; CYTOCHROME P450 1A2; CYTOCHROME P450 2A6; CYTOCHROME P450 2B6; CYTOCHROME P450 2C19; CYTOCHROME P450 2D6; CYTOCHROME P450 3A4; DIMETHYLANILINE MONOOXYGENASE; FLAVIN CONTAINING MONOOXYGENASE 1; KETOCONAZOLE; LORCASERIN; N HYDROXYLORCASERIN; RECOMBINANT ENZYME; UNCLASSIFIED DRUG;

ARTICLE; BIOTRANSFORMATION; CATALYSIS; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG METABOLISM; DRUG STRUCTURE; ENZYME ACTIVITY; ENZYME ANALYSIS; ENZYME KINETICS; HUMAN; HUMAN CELL; HUMAN TISSUE; HYDROXYLATION; IN VITRO STUDY; LIVER MICROSOME; PRIORITY JOURNAL; PROTEIN EXPRESSION;

BENZAZEPINES; BIOTRANSFORMATION; CATALYSIS; CYTOCHROME P-450 ENZYME SYSTEM; HUMANS; METABOLIC DETOXICATION, PHASE I; MICROSOMES, LIVER; OXYGENASES; RECEPTOR, SEROTONIN, 5-HT2C; SEROTONIN 5-HT2 RECEPTOR AGONISTS;

EID: 84863345375     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.111.043414     Document Type: Article

References (25)

1. Bjornsson TD, Callaghan JT, Einolf HJ, Fischer V, Gan L, Grimm S, Kao J, King SP, Miwa G, Ni L, et al. (2003) The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective. Drug Metab Dispos 31:815-823.
2. Cashman JR (2000) Human flavin-containing monooxygenase: substrate specificity and role in drug metabolism. Curr Drug Metab 1:181-191.
3. Chen WG, Xu J, Gwathney W, Prosser W, Morgan M, Cerny MA, Chen C, Sadeque AJM, and Shanahan W (2008) Metabolism, pharmacokinetics, and excretion of lorcaserin, a novel selective serotonin 5HT2C receptor agonist, in healthy male volunteers [abstract]. Drug Metab Rev 40 (Suppl 3):205.
4. Dolphin CT, Cullingford TE, Shephard EA, Smith RL, and Phillips IR (1996) Differential developmental and tissue-specific regulation of expression of the genes encoding three members of the flavin-containing monooxygenase family of man, FMO1, FMO3 and FM04. Eur J Biochem 235:683-689. (Pubitemid 26060969)
5. Guengerich FP (1995) Structure, mechanism and biochemistry, in Cytochrome P450 (de Montellano POR ed) pp 473-515, Plenum Press, New York.
6. Hodgson E and Goldstein JA (2001) Metabolism of toxicants: phase I reactions and pharmacogenetics, in Introduction to Biochemical Toxicology, 3rd Ed. (Hodgson E and Smart RC, eds) pp 67-112, John Wiley and Sons Inc., New York.
7. Krueger SK and Williams DE (2005) Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism. Pharmacol Ther 106:357-387. (Pubitemid 40726294)
8. Lawton MP, Cashman JR, Cresteil T, Dolphin CT, Elfarra AA, Hines RN, Hodgson E, Kimura T, Ozols J, and Phillips IR (1994) A nomenclature for the mammalian flavin-containing monooxygenase gene family based on amino acid sequence identities. Arch Biochem Biophys 308:254-257. (Pubitemid 24172630)
9. Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R, Waxman DJ, Waterman MR, Gotoh O, Coon MJ, Estabrook RW, et al. (1996) P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 6:1-42. (Pubitemid 26096749)
10. Newton DJ, Wang RW, and Lu AY (1995) Cytochrome P450 inhibitors. Evaluation of specificities in the in vitro metabolism of therapeutic agents by human liver microsomes. Drug Metab Dispos 23:154-158.
11. Ogilvie BW, Usuki E, Yerino P, and Parkinson A (2008) In vitro approaches for studying the inhibition of drug-metabolizing enzymes and identifying the drug-metabolizing enzymes responsible for the metabolism of drug (reaction phenotyping) with emphasis on cytochrome P450, in Drug-Drug Interactions, (Rodrigues AD ed) pp 231-358, Informa Healthcare, Yew York.
12. Phillips IR, Dolphin CT, Clair P, Hadley MR, Hutt AJ, McCombie RR, Smith RL, and Shephard EA (1995) The molecular biology of the flavin-containing monooxygenases of man. Chem Biol Interact 96:17-32.
13. Rawden HC, Kokwaro GO, Ward SA, and Edwards G (2000) Relative contribution of cytochromes P-450 and flavin-containing monoxygenases to the metabolism of albendazole by human liver microsomes. Br J Clin Pharmacol 49:313-322. (Pubitemid 30195273)
14. Rodrigues AD (1999a) Applications of heterologous expressed and purified human drug-metabolizing enzymes: an industrial perspective, in Handbook of Drug Metabolism (Wolf TE ed) pp 279-320, Marcel Dekker, New York.
15. Rodrigues AD (1999b) Integrated cytochrome P450 reaction phenotyping: attempting to bridge the gap between cDNA-expressed cytochromes P450 and native human liver microsomes. Biochem Pharmacol 57:465-480.
16. Sadeque AJ, Eddy AC, Meier GP, and Rettie AE (1992) Stereoselective sulfoxidation by human flavin-containing monooxygenase. Evidence for catalytic diversity between hepatic, renal, and fetal forms. Drug Metab Dispos 20:832-839.
17. Sadeque AJ, Thummel KE, and Rettie AE (1993) Purification of macaque liver flavin-containing monooxygenase: a form of the enzyme related immunochemically to an isozyme expressed selectively in adult human liver. Biochim Biophys Acta 1162:127-134. (Pubitemid 23071410)
18. Segel HI (1976) Biochemical Calculations, 2nd Ed., John Wiley & Sons, Ltd., New York.
19. Shimada T, Yamazaki H, Mimura M, Inui Y, and Guengerich FP (1994) Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 270:414-423. (Pubitemid 24229655)
20. Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, Chen RR, Park DM, Prieto EB, Gallardo CS, et al. (2008) Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity. J Med Chem 51:305-313.
21. Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E, Stubbe S, Bays H, Shanahan WR, and Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) Study Group (2010) Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 363:245-256.
22. Venkatakrishnan K, von Moltke LL, Obach RS, and Greenblatt DJ (2003) Drug metabolism and drug interactions: application and clinical value of in vitro models. Curr Drug Metab 4:423-459. (Pubitemid 37279366)
23. Wrighton SA and Ring BJ (1994) Inhibition of human CYP3A catalyzed 1′-hydroxymidazolam formation by ketoconazole, nifedipine, erythromycin, cimetidine and nizatidine. Pharm Res 11:921-924. (Pubitemid 24210633)
24. Yeung CK, Lang DH, Thummel KE, and Rettie AE (2000) Immunoquantitation of FMO1 in human liver, kidney, and intestine. Drug Metab Dispos 28:1107-1111. (Pubitemid 30660367)
25. Ziegler DM (1991) The 1990 Bernard B. Brodie Award Lecture. Unique properties of the enzymes of detoxication. Drug Metab Dispos 19:847-852.